Although age-dependent alterations in urinary magnesium (Mg2+) excretion have been described, the underlying mechanism remains elusive. As heritability significantly contributes to variations in urinary Mg2+ excretion, we measured urinary Mg2+ excretion at different ages in a cohort of genetically variable Diversity Outbred (DO) mice. Compared with animals aged 6 mo, an increase in Mg2+ excretion was observed at 12 and 18 mo. Quantitative trait locus (QTL) analysis revealed an association of a locus on chromosome 10 with Mg2+ excretion at 6 mo of age, with Oit3 (encoding oncoprotein-induced transcript 3; OIT3) as our primary candidate gene. To study the possible role of OIT3 in renal Mg2+ handling, we generated and characterized Oit3 knockout (Oit3-/-) mice. Although a slightly lower serum Mg2+ concentration was present in male Oit3-/- mice, this effect was not observed in female Oit3-/- mice. In addition, urinary Mg2+ excretion and the expression of renal magnesiotropic genes were unaltered in Oit3-/- mice. For animals aged 12 and 18 mo, QTL analysis revealed an association with a locus on chromosome 19, which contains the gene encoding TRPM6, a known Mg2+ channel involved in renal Mg2+ reabsorption. Comparison with RNA sequencing (RNA-Seq) data revealed that Trpm6 mRNA expression is inversely correlated with the QTL effect, implying that TRPM6 may be involved in age-dependent changes in urinary Mg2+ excretion in mice. In conclusion, we show here that variants in Oit3 and Trpm6 are associated with urinary Mg2+ excretion at distinct periods of life, although OIT3 is unlikely to affect renal Mg2+ handling.NEW & NOTEWORTHY Aging increased urinary magnesium (Mg2+) excretion in mice. We show here that variation in Oit3, a candidate gene for the locus associated with Mg2+ excretion in young mice, is unlikely to be involved as knockout of Oit3 did not affect Mg2+ excretion. Differences in the expression of the renal Mg2+ channel TRPM6 may contribute to the variation in urinary Mg2+ excretion in older mice.

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Proton pump inhibitors (PPIs) are commonly used for many gastrointestinal issues, such as gastroesophageal reflux disease (GERD), peptic ulcer disease, and Zollinger-Ellison syndrome. Many patients are on life-long daily therapy with this class of medications. The adverse effects of long-term use of PPI have been studied, and over the last two decades, a link between hypomagnesemia and PPI has been established. In addition, other electrolyte derangements can also ensue, such as hypokalemia and hypocalcemia. Losses through the gastrointestinal or renal systems may also be responsible for this electrolyte disturbance. In this case, we present a \"perfect storm\" of a patient who, in addition to having ongoing gastrointestinal losses through an ostomy, had severe hypomagnesemia to less than 1 mg/dL compounded by PPI use. Through its unique mechanism of action on intestinal epithelial cells, PPI use in certain settings can potentially be catastrophic. Severe hypomagnesemia may manifest as tetany, convulsions, tremors, arrhythmias, or torsades de pointes.

HOMG1 (hypomagnesemia 1, intestinal) or hypomagnesemia with secondary hypocalcemia is a rare autosomal recessive disorder of magnesium metabolism, characterized by impaired magnesium absorption. This disorder may mimic other conditions presenting with neonatal seizures. Here, we report an infant diagnosed to have hypomagnesemia with secondary hypocalcemia due to novel variants in TRPM6 gene.

Magnesium is ubiquitous in nature. It sits at the origin of the food chain, occupying the center of chlorophyl in plants. In humans, magnesium is critical to diverse molecular and catalytic processes, including energy transfer and maintenance of the genome. Despite its abundance, hypomagnesemia is common and often goes undiagnosed. This is in spite of epidemiologic data linking low magnesium with chronic diseases including diabetes mellitus. Clinically significant hypermagnesemia is encountered less frequently, but the presentation may be dramatic. Advances in molecular biology and the elucidation of the genetic causes of magnesium disorders have enhanced our understanding of their pathophysiology. Treatment approaches are also changing. The repurposing of newer medications, such as sodium/glucose cotransporter 2 inhibitors, offers new therapeutic options. In this review we integrate knowledge in this rapidly evolving field to provide clinicians and trainees with a resource for approaching common clinical scenarios involving magnesium disorders.

The implementation of array comparative genomic hybridisation (array-CGH) allows us to describe new microdeletion/microduplication syndromes which were previously not identified. 9q21.13 microdeletion syndrome is a genetic condition due to the loss of a critical genomic region of approximately 750kb and includes several genes, such as RORB and TRPM6. Here, we report a case of a 7-year-old boy affected by 9q21.13 microdeletion syndrome. He presents with global developmental delay, intellectual disability, autistic behaviour, seizures and facial dysmorphism. Moreover, he has severe myopia, which was previously reported in only another patient with 9q21.13 deletion, and brain anomalies which were never described before in 9q21.13 microdeletion syndrome. We also collect 17 patients from a literature search and 10 cases from DECIPHER database with a total number of 28 patients (including our case). In order to better investigate the four candidate genes RORB, TRPM6, PCSK5, and PRUNE2 for neurological phenotype, we make, for the first time, a classification in four groups of all the collected 28 patients. This classification is based both on the genomic position of the deletions included in the 9q21.3 locus deleted in our patient and on the different involvement of the four-candidate gene. In this way, we compare the clinical problems, the radiological findings, and the dysmorphic features of each group and of all the 28 patients in our article. Moreover, we perform the genotype-phenotype correlation of the 28 patients to better define the syndromic spectrum of 9q21.13 microdeletion syndrome. Finally, we propose a baseline ophthalmological and neurological monitoring of this syndrome.

Magnesium is crucial for various cellular and enzymatic processes, yet it often is overlooked or underappreciated. Hypomagnesemia, a deficiency of magnesium in the blood, is a frequent problem in cancer patients and can lead to severe symptoms and morbidity. In this review, we provide an in-depth analysis of the physiology and regulation of magnesium, and signs and symptoms of hypomagnesemia in cancer patients. We also examine the causes and mechanisms of magnesium imbalances in cancer patients, specifically focusing on cancer-specific therapies that can lead to hypomagnesemia. Finally, we provide updates on the management of hypomagnesemia, including oral and parenteral supplementation, as well as the role of drugs in cases that are resistant to treatment. This review aims to raise awareness among health care providers caring for cancer patients about the significance of monitoring magnesium levels in cancer patients and function as a guide. Future clinical studies should focus on magnesium monitoring, its impact on cancer progression, and its potential for preventing acute kidney injury.

TRPM6 is predominantly expressed in the kidney and colon and encodes a protein containing an ion channel domain and a protein kinase domain. It is crucial for magnesium homeostasis and plays important roles in epithelial magnesium transport and the active magnesium absorption. In this study, we present a 70-day-old Iranian female patient from consanguineous parents with hypomagnesemia and secondary hypocalcemia. She presented with seizures 19 days after birth and refractory watery non-bloody diarrhea. She consequently had failure to thrive. Other features included hypotonia, wide anterior fontanel, ventriculomegaly, and pseudotumor cerebri following administration of nalidixic acid. She had severe hypomagnesemia and hypocalcemia which were treated with magnesium and calcium supplementation. Despite initial unstable response to supplemental magnesium, she eventually improved and the diarrhea discontinued. The patient was discharged by magnesium and calcium therapy. At the last follow-up at age 2.5 years, the patient remained well without any recurrence or complication. Genetic testing by whole-exome sequencing revealed a novel homozygous frameshift insertion-deletion (indel) variant in exon 26 of the TRPM6 gene, c.3693-3699del GCAAGAG ins CTGCTGTTGACATCTGCT, p.L1231Ffs*36. Segregation analysis revealed the TRPM6 heterozygous variant in both parents. Patients with biallelic TRPM6 pathogenic variants typically exhibit hypomagnesemia with secondary hypocalcemia and present with neurologic manifestations including seizures. In some patients, this is also complicated by chronic diarrhea and failure to thrive. Long-term complications are rare and most of the patients show a good prognosis with supplemental magnesium therapy.

UNASSIGNED: Transient receptor potential melastatin (TRPM) channel is involved in cell proliferation and cell survival. Eight members (TRPM1-8) are within the TRPM subfamily. The current study is aimed to investigate TRPM6 expression in human oral carcinogenesis.
UNASSIGNED: Sixty-six oral squamous cell carcinomas (OSCCs), 47 oral potentially malignant disorders (OPMD) with moderate-severe epithelial dysplasia (ED), 28 OPMD with mild ED, and 33 normal oral mucosa (NOM) samples were subjected to immunohistochemical staining. Two human oral cancer cell lines (OCCLs), an oral premalignant cell line (DOK), and a normal oral keratinocyte culture (HOK) were used for Western blot analysis. OCCLs were evaluated for proliferation, migration, invasion assays, and intracellular calcium concentration.
UNASSIGNED: TRPM6 protein expression in OSCC was significantly increased as compared with normal samples. Protein expression of TRPM6 in OCCLs was significantly higher as compared with HOK. Significant decreases in degrees of proliferation, migration, invasion, and intracellular calcium concentration were noted in OCCLs with TRPM6 siRNA transfection as compared with those without transfection. Significantly increased TRPM6 protein level was noted in OPMD with moderate-severe ED as compared with those with mild ED.
UNASSIGNED: Our results implicate that TRPM6 overexpression is potentially related to human oral carcinogenesis.

Disruption of small intestinal Mg2+ absorption has been reported as the underlying mechanism of proton pump inhibitor-induced hypomagnesemia (PPIH); hence, this study evaluated the expression, localization, phosphorylation, and oxidation of transient receptor potential melastatin 6 (TRPM6) and TRPM7 in the small intestine of rats subjected to PPIH. The expression and localization of cyclin M4 (CNNM4) was also analyzed. We show that, compared to control rats, membrane expression of the TRPM6/7 heterodimer and TRPM7 was markedly lower in the duodenum and the jejunum of PPIH rats; in contrast, expression of membrane TRPM6 and CNNM4 was higher in these organs. Mass spectrometric analysis of TRPM6 demonstrated hyper-phosphorylation, especially T1851, and hyper-oxidation at M1755, both of which can suppress its channel permeability. Further, hypo-phosphorylation of S141 and the dimerization motif domain of TRPM6 in PPIH rats might be involved in lower TRPM6/7 heterodimer expression. Hypo-phosphorylation, especially at S138 and S1360 in TRPM7 from PPIH rats disrupted stability of TRPM7 at the cell membrane; hyper-oxidation of TRPM7 was also observed. These results help explain the mechanism underlying the disruption of small intestinal Mg2+ absorption in PPIH.